Scientists show proof-of-principal for silencing extra chromosome responsible for Down syndrome

July 17, 2013 — Scientists at UMass Medical School are the first to establish that a naturally occurring X chromosome “off switch” can be rerouted to neutralize the extra chromosome responsible for trisomy 21, also known as Down syndrome, a genetic disorder characterized by cognitive impairment.The discovery provides the first evidence that the underlying genetic defect responsible for Down syndrome can be suppressed in cells in culture (in vitro). This paves the way for researchers to study the cell pathologies and identify genome-wide pathways implicated in the disorder, a goal that has so far proven elusive. Doing so will improve scientists’ understanding of the basic biology underlying Down syndrome and may one day help establish potential therapeutic targets for future therapies. Details of the study by Jiang et al. were published online in Nature.”The last decade has seen great advances in efforts to correct single-gene disorders, beginning with cells in vitro and in several cases advancing to in vivo and clinical trials,” said lead author Jeanne B. Lawrence, PhD, professor of cell & developmental biology. “By contrast, genetic correction of hundreds of genes across an entire extra chromosome has remained outside the realm of possibility. Our hope is that for individuals living with Down syndrome, this proof-of-principal opens up multiple exciting new avenues for studying the disorder now, and brings into the realm of consideration research on the concept of ‘ ‘chromosome therapy’ in the future.”Humans are born with 23 pairs of chromosomes, including two sex chromosomes, for a total of 46 in each cell. People with Down syndrome are born with three (rather than two) copies of chromosome 21, and this “trisomy 21” causes cognitive disability, early-onset Alzheimer’s disease; and a greater risk of childhood leukemia, heart defects and immune and endocrine system dysfunction. Unlike for genetic disorders caused by a single gene, genetic correction of a whole chromosome in trisomic cells has been beyond the realm of possibility, even in cultured cells.Harnessing the power of the RNA gene called XIST, which is normally responsible for turning off one of the two X chromosomes found in female mammals, UMMS scientists have shown that the extra copy of chromosomes 21 responsible for Down syndrome can be silenced in the laboratory using patient-derived stem cells.The natural function of the XIST gene, located on the X chromosome, is to effectively silence one of the two X chromosomes in female cells, making expression of X-linked genes similar to that of men, who have just one X chromosome. …

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Seizures late in life may be an early sign of Alzheimer’s disease

July 8, 2013 — Patients with epilepsy who had amnestic mild cognitive impairment (aMCI) or Alzheimer disease (AD) presented earlier with cognitive decline than patients who did not have epilepsy, according to a report published by JAMA Neurology, a JAMA Network publication.AD increases a patient’s risk of risk of seizures, and patients with AD and seizure disorders have greater cognitive impairment, more rapid progression of symptoms and more severe neuronal loss at autopsy than those without seizures, according to the study background.”Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated and may reflect pathogenic processes that also contribute to other aspects of the illness,” authors note in the study by Keith A. Vossel, M.D., M.Sc., of the Gladstone Institute of Neurological Disease, San Francisco, Calif., and colleagues.The study included 54 patients with a diagnosis of aMCI plus epilepsy (n=12), AD plus epilepsy (n=35) and AD plus subclinical epileptiform activity (n=7).Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs. 71.1 years). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs. 70.3 years), according to the results.”Careful identification and treatment of epilepsy in such patients may improve their clinical course,” the study concludes.

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Non-invasive brain stimulation helps stroke patients gain prolonged language recovery

July 2, 2013 — A new study details of a technique developed by researchers to improve language function in stroke patients with chronic speech-language impairment. The study is published in the Journal of Visualized Experiments (JoVE).Strokes occur when a brain clot blocks blood flow in parts of the brain, essentially starving groups of neurons of oxygen, which is necessary for normal function. Nearly 130,000 of the 795,000 strokes Americans suffer annually result in death, accounting for roughly 5% of deaths in the U.S. The remaining 665,000 stroke patients suffer a wide variety of side effects ranging from complete loss of motor function to loss of speech to a catatonic state. Because of the horrific nature of these cerebrovascular events and their consequences, many clinical researchers focus on prevention, rehabilitation and restoration of function for stroke victims.A technique developed through these efforts utilizes transcranial magnetic stimulation (TMS) to improve language function in stroke patients with chronic aphasia. Patients who have undergone this procedure have previously reached a plateau in their ability to produce fluent language, despite signs of understanding and frustration at their inability to communicate.”The heart of our work is to use non-invasive brain stimulation… to modulate cortical networks that we think are in flux. We think that those circuits in the brain do remodel and that we can tweak them further using non-invasive stimulation,” explains Roy Hamilton, M.D., the co-director of the Laboratory for Cognition and Neural Stimulation at the University of Pennsylvania Medical School. He continues, “For most people the left hemisphere plays a dominant role in our language capacity. The brain does have the capacity to reorganize itself and rework some of the network and geography that represents specific cognitive skills.”Transcranial magnetic stimulation was first successfully performed in 1985 by Anthony Barker and his colleagues in Sheffield, UK. The technique takes advantage of an aspect of physics derived from the Biot-Savart Law, which states that a current running through a wire generates a magnetic field. …

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PET finds increased cognitive reserve levels in highly educated pre-Alzheimer’s patients

June 3, 2013 — Highly educated individuals with mild cognitive impairment that later progressed to Alzheimer’s disease cope better with the disease than individuals with a lower level of education in the same situation, according to research published in the June issue of The Journal of Nuclear Medicine. In the study “Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project,”neural reserve and neural compensation were both shown to play a role in determining cognitive reserve, as evidenced by positron emission tomography (PET).Cognitive reserve refers to the hypothesized capacity of an adult brain to cope with brain damage in order to maintain a relatively preserved functional level. Understanding the brain adaptation mechanisms underlying this process remains a critical question, and researchers of this study sought to investigate the metabolic basis of cognitive reserve in individuals with higher (more than 12 years) and lower (less than 12 years) levels of education who had mild cognitive impairment that progressed to Alzheimer’s disease, also known as prodromal Alzheimer’s disease.”This study provides new insight into the functional mechanisms that mediate the cognitive reserve phenomenon in the early stages of Alzheimer’s disease,” said Silvia Morbelli, MD, lead author of the study. “A crucial role of the dorso-lateral prefrontal cortex was highlighted by demonstrating that this region is involved in a wide fronto-temporal and limbic functional network in patients with Alzheimer’s disease and high education, but not in poorly educated Alzheimer’s disease patients.”In the study, 64 patients with prodromal Alzheimer’s disease and 90 control subjects — coming from the brain PET project (chaired by Flavio Nobili, MD, in Genoa, Italy) of the European Alzheimer Disease Consortium — underwentbrain 18F-FDG PET scans. Individuals were divided into a subgroup with a low level of education (42 controls and 36 prodromal Alzheimer’s disease patients) and a highly educated subgroup (40 controls and 28 prodromal Alzheimer’s disease patients). Brain metabolism was compared between education-matched groups of patients and controls, and then between highly and poorly educated prodromal Alzheimer’s disease patients.Higher metabolic activity was shown in the dorso-lateral prefrontal cortex for prodromal Alzheimer’s disease patients. More extended and significant correlations of metabolism within the right dorso-lateral prefrontal cortex and other brain regions were found with highly educated than less educated prodromal Alzheimer’s disease patients or even highly educated controls.This result suggests that neural reserve and neural compensation are activated in highly educated prodromal Alzheimer’s disease patients. Researchers concluded that evaluation of the implication of metabolic connectivity in cognitive reserve further confirms that adding a comprehensive evaluation of resting 18F-FDG PET brain distribution to standard inspection may allow a more complete comprehension of Alzheimer’s disease pathophysiology and possibly may increase 18F-FDG PET diagnostic sensitivity.”This work supports the notion that employing the brain in complex tasks and developing our own education may help in forming stronger ‘defenses’ against cognitive deterioration once Alzheimer knocks at our door,” noted Morbelli.”It’s possible that, in the future, a combined approach evaluating resting metabolic connectivity and cognitive performance can be used on an individual basis to better predict cognitive decline or response to disease-modifying therapy.”

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